We have developed an immunotoxin SS1P that targets ovarian cancers, mesotheliomas and pancreatic cancers that is currently in clinical trials. In collaboration with our CRADA partner ENZON we are carrying out laboratory experiments to produce improved forms of SS1P. One approach is to modify SS1P with high molecular weight polyethylene glycol to decrease immunogenicity and increase half-life in the circulation. Many mutants of SS1P have been produced to allow site-specific modification with PEG. Several of these have been modified with PEG by ENZON and have increased anti-tumor activity in mice.[unreadable] [unreadable] Hematopoietic Tumors- Immunotoxin BL22 has shown excellent clinical activity in patients with Hairy Cell Leukemia. To increase the usefulness of BL22 in other leukemias and lymphomas we have mutated the protein to increase its affinity for CD22 and also mutated the toxin to increase its ability to reach the cytosol and kill target cells. An improved form of BL22 called HA22 is being prepared for a clinical trial in chronic lymphocytic leukemia. Other high affinity forms of BL22 are now being prepared. CD30 is expressed on cells from Hodgkin's disease and anaplastic large cell lymphoma. A series of new antibodies to CD30 have been produced. Two of these MAbs bind to an epitope not present on soluble CD30 and should be especially useful for targeted therapy.[unreadable] [unreadable] The IRTA2 gene is expressed in many lymphomas. We have prepared monoclonal antibodies to IRTA2 and shown that the protein is expressed on the surface of several B cell leukemias and lymphomas. We have used these MAbs to develop an ELISA for IRTA2. Soluble IRTA2 protein is present in human serum and its levels are elevated in Hairy Cell Leukemia and some other leukemias and lymphomas.[unreadable] [unreadable] We are exploring new ways to enhance immunotoxin action by increasing its penetration into tumors. The effectiveness of immunotoxins in mice is increased by prior administration of Avastin, an antibody that inactivates VEGF.[unreadable]